High-Density Lipoprotein-Targeted Therapy for Coronary Heart Disease: is the HDL Hypothesis Operational or Defunct?

Supported by evidence from basic science, clinical, and epidemiological studies, the high-density lipoprotein (HDL) hypothesis posits that reduction in HDL levels may accelerate the development of coronary heart disease (CHD). HDL may also exert cardiovascular protection via anti-oxidative, anti-thrombotic, anti-inflammatory, and anti-apoptotic properties. However, controversial results from clinical trials involving HDL-raising interventions have cast doubts on the validity of HDL hypothesis. The coevolution of HDL physiology and CHD pathogenesis has prompted the revision of hypothesis, with an alternative focus on the functionality of HDL particles. Instead of raising the quantity of HDL, improving the quality of HDL by promoting reverse cholesterol transport may be a more appropriate strategy in preventing adverse cardiovascular events. Preliminary data suggest that administration of apolipoprotein A1 mimetic peptides and reconstituted HDL particles could be safe and effective in promoting plaque stabilization and regression. Future studies are warranted to clarify the effect of HDL subspecies on atherosclerosis and determine whether the effect could translate into cardiovascular benefits.